ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000007.13) (NC_000007.14)

Haploinsufficiency phenotype comments:

There is a significant amount of evidence suggesting that loss of KCNH2 results in Long QT syndrome (LQTS). In addition to the evidence above, Itoh et al 2016 (PMID: 26669661) report 280 KCNH2 variants in families with LQTS; 95/280 were nonsense, frameshift or splice site variants (>100 families with multiple affected individuals) (Supplementary Table 2). Stattin et al 2012 (PMID: 23098067 ) reports 3 additional affected probands with truncating variants. HGMD also catalogs a number of putative loss of function variants, including: 70 disease causing nonsense variants,17 disease causing splice site variants (+/-2), 6 large deletions (multiple exons), and 141 disease causing frame shift variants. Of note, large deletions involving KCNH2 in addition to other genes have also been observed in individuals diagnosed with Long QT syndrome. Barc et al (2011) (PMID: 21185499) studied 93 patients with LQTS who had experienced symptoms such as syncope, arrhythmia, and cardiac arrest. Two probands were found with deletion in KCNH2. The proband of Family 1 was 23 years old with a 650 kb deletion of exons 4-14 (+19 other genes centromeric to KCNH2). Six other carrier family members had LQTS but were asymptomatic. The proband of Family 2 was 28 years old with a 145 kb deletion of the entire KCNH2 and ABP1 genes. The deletion was also found in her affected mother and "healthy" brother.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity